Neurotoxic and neuroprotective metabolites of kynurenine in patients with renal cell carcinoma treated with interferon-alpha: course and relationship with psychiatric status.
OBJECTIVE
Immunotherapy with interferon-alpha (IFN-alpha) is associated with psychiatric side-effects, including depression. One of the putative pathways underlying these psychiatric side-effects involves tryptophan (TRP) metabolism. Cytokines including IFN-alpha induce the enzyme indoleamine 2,3-dioxygenase (IDO), which converts TRP to kynurenine (KYN), leading to a shortage of serotonin (5-HT). In addition, the production of neurotoxic metabolites of KYN such as 3-hydroxykynurenine and quinolinic acid (QA) might increase and contribute to IFN-alpha-induced psychopathology. In contrast, other catabolites of KYN, such as kynurenic acid (KA), are thought to have neuroprotective properties.


METHODS
In a group of 24 patients treated with standard IFN-alpha for metastatic renal cell carcinoma (RCC), combined psychiatric and laboratory assessments were performed at baseline, 4 and 8 weeks, and at 6 months.


RESULTS
No psychopathology was observed, despite an increase in neurotoxic challenge as reflected in indices for the balance between neurotoxic and neuroprotective metabolites of KYN.


CONCLUSIONS
The present hypothesis that a shift in the balance between neurotoxic and neuroprotective metabolites of KYN underlies the neuropsychiatric side-effects of IFN-alpha-based immunotherapy, is neither supported nor rejected.
Van Gool
Arthur R
AR
Department of Psychiatry, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. a.vangool@erasmusmc.nl
Verkerk
Robert
R
Fekkes
Durk
D
Bannink
Marjolein
M
Sleijfer
Stefan
S
Kruit
Wim H J
WH
van der Holt
Bronno
B
Scharpé
Simon
S
Eggermont
Alexander M M
AM
Stoter
Gerrit
G
Hengeveld
Michiel W
MW
D000328:Adult; D000368:Aged; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy*; D003865:Major Depressive Disorder / Q000097:blood / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000097:blood*; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000097:blood*; D009483:Neuropsychological Tests; D009498:Neurotoxins / Q000097:blood*; D017378:Quinolinic Acid / Q000097:blood*
D007155:Immunologic Factors; D016898:Interferon-alpha; D018696:Neuroprotective Agents; D009498:Neurotoxins; C005045:3-hydroxykynurenine; D007737:Kynurenine; D017378:Quinolinic Acid